Transcriptomic dysregulation and autistic-like behaviors in Kmt2c haploinsufficient mice rescued by an LSD1 inhibitor.

Recent studies have consistently demonstrated that the regulation of chromatin and gene transcription plays a pivotal role in the pathogenesis of neurodevelopmental disorders. Among many genes involved in these pathways, KMT2C, encoding one of the six known histone H3 lysine 4 (H3K4) methyltransferases in humans and rodents, was identified as a gene whose heterozygous loss-of-function variants are causally associated with autism spectrum disorder (ASD) and the Kleefstra syndrome phenotypic spectrum. However, little is known about how KMT2C haploinsufficiency causes neurodevelopmental deficits and how these conditions can be treated. To address this, we developed and analyzed genetically engineered mice with a heterozygous frameshift mutation of Kmt2c (Kmt2c+/fs mice) as a disease model with high etiological validity. In a series of behavioral analyses, the mutant mice exhibit autistic-like behaviors such as impairments in sociality, flexibility, and working memory, demonstrating their face validity as an ASD model. To investigate the molecular basis of the observed abnormalities, we performed a transcriptomic analysis of their bulk adult brains and found that ASD risk genes were specifically enriched in the upregulated differentially expressed genes (DEGs), whereas KMT2C peaks detected by ChIP-seq were significantly co-localized with the downregulated genes, suggesting an important role of putative indirect effects of Kmt2c haploinsufficiency. We further performed single-cell RNA sequencing of newborn mouse brains to obtain cell type-resolved insights at an earlier stage. By integrating findings from ASD exome sequencing, genome-wide association, and postmortem brain studies to characterize DEGs in each cell cluster, we found strong ASD-associated transcriptomic changes in radial glia and immature neurons with no obvious bias toward upregulated or downregulated DEGs. On the other hand, there was no significant gross change in the cellular composition. Lastly, we explored potential therapeutic agents and demonstrate that vafidemstat, a lysine-specific histone demethylase 1 (LSD1) inhibitor that was effective in other models of neuropsychiatric/neurodevelopmental disorders, ameliorates impairments in sociality but not working memory in adult Kmt2c+/fs mice. Intriguingly, the administration of vafidemstat was shown to alter the vast majority of DEGs in the direction to normalize the transcriptomic abnormalities in the mutant mice (94.3 and 82.5% of the significant upregulated and downregulated DEGs, respectively, P < 2.2 × 10-16, binomial test), which could be the molecular mechanism underlying the behavioral rescuing. In summary, our study expands the repertoire of ASD models with high etiological and face validity, elucidates the cell-type resolved molecular alterations due to Kmt2c haploinsufficiency, and demonstrates the efficacy of an LSD1 inhibitor that might be generalizable to multiple categories of psychiatric disorders along with a better understanding of its presumed mechanisms of action.

Functional and behavioral effects of de novo mutations in calcium-related genes in patients with bipolar disorder.

Bipolar disorder is a common mental illness occurring in approximately 1% of individuals and requires lifelong treatment. Although genetic factors are known to contribute to this disorder, the genetic architecture has not yet been completely clarified. Our initial trio-based exome sequencing study of bipolar disorder showed enrichment of de novo, loss-of-function (LOF) or protein-altering mutations in a combined group with bipolar I and schizoaffective disorders, and the identified de novo mutations were enriched in calcium-related genes. These findings suggested a role for de novo mutations in bipolar disorder. The validity of these statistical associations will be strengthened if the functional impact of the mutations on cellular function and behavior are identified. In this study, we focused on two de novo LOF mutations in calcium-related genes, EHD1 and MACF1, found in patients with bipolar disorder. We first showed that the EHD1 mutation resulted in a truncated protein with diminished effect on neurite outgrowth and inhibited endocytosis. Next, we used CRISPR/Cas9 to establish two knock-in mouse lines to model the in vivo effects of these mutations. We performed behavioral screening using IntelliCage and long-term wheel running analysis. Ehd1 mutant mice showed higher activity in the light phase. Macf1 mutant mice showed diminished attention and persistence to rewards. These behavioral alterations were similar to the phenotypes in previously proposed animal models of bipolar disorder. These findings endorse the possible role of de novo mutations as a component of the genetic architecture of bipolar disorder, which was suggested by the statistical evidence.

Brain-specific heterozygous loss-of-function of ATP2A2, endoplasmic reticulum Ca2+ pump responsible for Darier's disease, causes behavioral abnormalities and a hyper-dopaminergic state.

A report of a family of Darier's disease with mood disorders drew attention when the causative gene was identified as ATP2A2 (or SERCA2), which encodes a Ca2+ pump on the endoplasmic reticulum (ER) membrane and is important for intracellular Ca2+ signaling. Recently, it was found that loss-of-function mutations of ATP2A2 confer a risk of neuropsychiatric disorders including depression, bipolar disorder and schizophrenia. In addition, a genome-wide association study found an association between ATP2A2 and schizophrenia. However, the mechanism of how ATP2A2 contributes to vulnerability to these mental disorders is unknown. Here, we analyzed Atp2a2 heterozygous brain-specific conditional knockout (hetero cKO) mice. The ER membranes prepared from the hetero cKO mouse brain showed decreased Ca2+ uptake activity. In Atp2a2 heterozygous neurons, decays of cytosolic Ca2+ level were slower than control neurons after depolarization. The hetero cKO mice showed altered behavioral responses to novel environments and impairments in fear memory, suggestive of enhanced dopamine signaling. In vivo dialysis demonstrated that extracellular dopamine levels in the NAc were indeed higher in the hetero cKO mice. These results altogether indicate that the haploinsufficiency of Atp2a2 in the brain causes prolonged cytosolic Ca2+ transients, which possibly results in enhanced dopamine signaling, a common feature of mood disorders and schizophrenia. These findings elucidate how ATP2A2 mutations causing a dermatological disease may exert their pleiotropic effects on the brain and confer a risk for mental disorders.

Development of x-ray mirror foils using a hot plastic deformation process.

In this paper, we present a silicon reflector developed through a hot plastic deformation process and used as a lightweight, high-angular-resolution x-ray mirror. We deformed the silicon substrate using conical dies with a curvature radius of 100 mm. The measured radii of the reflector were approximately 100 µm greater than the design values. Due to a gap between the die and the reflector toward the edge, it is probable that the substrate did not reach the yield point, and an elastic spring back occurred. In addition, we have evaluated the x-ray imaging capability of the plastically deformed silicon reflector for the first time, to the best of our knowledge. The estimated angular resolution is 1.76 arc min from the entire reflector, and 0.52 arc min in the best region. For the enhancement of the imaging capability, we may improve the shape of die and determine the best parameter set for the deformation.

Effect of cognitive behavioral group therapy for recovery of self-esteem on community-living individuals with mental illness: Non-randomized controlled trial.

AIM: The aim of this study was to examine over a 12-month post-intervention period whether the participation of community-living individuals with mental illness in cognitive behavioral group therapy for recovery of self-esteem (CBGTRS) resulted in improved outcomes. METHODS: This was a non-randomized controlled trial. The participants were persons with mental illness who resided in communities in the Chugoku region of Japan. In total, 41 were assigned to an experimental group (CBGTRS intervention, 12 group sessions), and 21 to a control group. Outcome indices (self-esteem, moods, cognition, subjective well-being, psychiatric symptoms) were measured for the experimental group prior to intervention (T0), immediately post-intervention (T1), and at 3 (T2) and 12 (T3) months post-intervention. The control group was measured at the same intervals. RESULTS: For the experimental group, self-esteem scores at T1, T2, and T3 were significantly higher than at T0. Moods and cognition scores remained significantly low until T2. Scores for Inadequate Mental Mastery in the subjective well-being index had not decreased by T3. Confidence in Coping remained significantly high until T2. Psychiatric symptoms scores at T0, T1, T2, and T3 were significantly lower than at T0. The means and standard errors for self-esteem and Inadequate Mental Mastery increased until T3, and those for Tension-Anxiety, Depression-Dejection, and Confusion decreased until T2. CONCLUSION: From within-group trends and between-group differences in self-esteem, we conclude that CBGTRS may have a relatively long-term effect on self-esteem recovery. T2 is the turning point for moods and cognition; thus, follow-up is needed 3 months following the initial program.

Loss of function mutations in ATP2A2 and psychoses: A case report and literature survey.

AIM: Though genetic factors play a major role in the pathophysiology of psychoses including bipolar disorder (BD) and schizophrenia, lack of well-established causative genetic mutations hampers their neurobiological studies. Darier's disease, an autosomal dominant skin disorder caused by mutations of ATP2A2 on chromosome 12q23-24.1, encoding sarco/endoplasmic reticulum calcium transporting ATPase 2 (SERCA2), reportedly cosegregates with BD. A recent genome-wide association study showed an association of schizophrenia with ATP2A2. METHODS: We sequenced all coding regions of ATP2A2 in a newly identified patient with Darier's disease and BD. In addition, we performed a literature survey to examine whether likely gene disrupting (LGD) mutations are related to psychoses. RESULTS: We identified a rare heterozygous mutation, c.1288-6A>G, at the 3' end of intron 10 in the patient. A minigene splicing assay showed that this mutation introduces a new splice site causing a frameshift and premature stop codon. A literature survey of case reports of patients with Darier's disease and psychoses revealed that the rate of LGD mutations causing frameshift, altered splicing, gain of stop codon, or loss of start codon was significantly higher among the mutations harbored by these cases (9 of 11) than that of ATP2A2 mutations for which comorbidity of psychosis was not reported (107 of 237, P = 0.026). The only non-LGD mutation (p.C560R) reported in patients with Darier's disease and BD caused decreased ATP2A2 protein expression. CONCLUSION: These results suggest that psychoses in Darier's disease may be caused by a pleiotropic effect of loss-of-function mutations of ATP2A2.

Effects of N-acetyl-L-cysteine on target sites of hydroxylated fullerene-induced cytotoxicity in isolated rat hepatocytes.

The effects of N-acetyl-L-cysteine (NAC) on cytotoxicity caused by a hydroxylated fullerene [C60(OH)24], which is known a nanomaterial and/or a water-soluble fullerene derivative, were studied in freshly isolated rat hepatocytes. The exposure of hepatocytes to C60(OH)24 at a concentration of 0.1 mM caused time (0-3 h)-dependent cell death accompanied by the formation of cell blebs, loss of cellular ATP, and reduced glutathione (GSH) and protein thiol levels, as well as the accumulation of glutathione disulfide and malondialdehyde (MDA), indicating lipid peroxidation. Despite this, C60(OH)24-induced cytotoxicity was effectively prevented by NAC pretreatment ranging in concentrations from 1 to 5 mM. Further, the loss of mitochondrial membrane potential (MMP) and generation of oxygen radical species in hepatocytes incubated with C60(OH)24 were inhibited by pretreatment with NAC, which caused increases in cellular and/or mitochondrial levels of GSH, accompanied by increased levels of cysteine via enzymatic deacetylation of NAC. On the other hand, severe depletion of cellular GSH levels caused by diethyl maleate at a concentration of 1.25 mM led to the enhancement of C60(OH)24-induced cell death accompanied by a rapid loss of ATP. Taken collectively, these results indicate that pretreatment with NAC ameliorates (a) mitochondrial dysfunction linked to the depletion of ATP, MMP, and mitochondrial GSH level and (b) induction of oxidative stress assessed by reactive oxygen species generation, losses of intracellular GSH and protein thiol levels, and MDA formation caused by C60(OH)24, suggesting that the onset of toxic effects is at least partially attributable to a thiol redox-state imbalance as well as mitochondrial dysfunction related to oxidative phosphorylation.

Large-aperture focusing of x rays with micropore optics using dry etching of silicon wafers.

Large-aperture focusing of Al K(α) 1.49 keV x-ray photons using micropore optics made from a dry-etched 4 in. (100 mm) silicon wafer is demonstrated. Sidewalls of the micropores are smoothed with high-temperature annealing to work as x-ray mirrors. The wafer is bent to a spherical shape to collect parallel x rays into a focus. Our result supports that this new type of optics allows for the manufacturing of ultralight-weight and high-performance x-ray imaging optics with large apertures at low cost.

Exclusion of Kif1c as a candidate gene for anthrax toxin susceptibility.

Different strains of mice possess varying degrees of susceptibility to anthrax lethal toxin (LT). Previous studies have suggested a responsible locus Ltxs1 that contains 10 or more known genes, but functional relevance has been reported for two genes, Kif1c and Nalp1b. In this study, we attempted to determine the involvement of Kif1c in anthrax susceptibility using Kif1c knockout mice. We established Kif1c knockout mice with LT-sensitive 129/Sv-derived embryonic stem cells followed by 13 backcrosses with LT-resistant C57BL/6J mice (B6) to be congenic. These knockout mice and their primary macrophages showed significantly higher sensitivity to LT than wild-type B6. However, when we replaced the remaining 129/Sv genome adjacent to the targeted Kif1c locus with the B6 genome, this sensitivity was lost. This suggested that the sensitivity to LT in the originally established Kif1c knockout mice was not due to the loss of the Kif1c gene, but was because of the presence of the 129/Sv-derived genes adjacent to the disrupted Kif1c locus. Thus, Kif1c was excluded as a candidate anthrax susceptibility gene.

Ntrk1 mutation co-segregating with bipolar disorder and inherited kidney disease in a multiplex family causes defects in neuronal growth and depression-like behavior in mice.

Previously, we reported a family in which bipolar disorder (BD) co-segregates with a Mendelian kidney disorder linked to 1q22. The causative renal gene was later identified as MUC1. Genome-wide linkage analysis of BD in the family yielded a peak at 1q22 that encompassed the NTRK1 and MUC1 genes. NTRK1 codes for TrkA (Tropomyosin-related kinase A) which is essential for development of the cholinergic nervous system. Whole genome sequencing of the proband identified a damaging missense mutation, E492K, in NTRK1. Induced pluripotent stem cells were generated from family members, and then differentiated to neural stem cells (NSCs). E492K NSCs had reduced neurite outgrowth. A conditional knock-in mouse line, harboring the point mutation in the brain, showed depression-like behavior in the tail suspension test following challenge by physostigmine, a cholinesterase inhibitor. These results are consistent with the cholinergic hypothesis of depression. They imply that the NTRK1 E492K mutation, impairs cholinergic neurotransmission, and may convey susceptibility to bipolar disorder.

Glutamine-induced signaling pathways via amino acid receptors in enteroendocrine L cell lines.

Glucagon-like peptide-1 (GLP-1), secreted by gastrointestinal enteroendocrine L cells, induces insulin secretion and is important for glucose homeostasis. GLP-1 secretion is induced by various luminal nutrients, including amino acids. Intracellular Ca2+ and cAMP dynamics play an important role in GLP-1 secretion regulation; however, several aspects of the underlying mechanism of amino acid-induced GLP-1 secretion are not well characterized. We investigated the mechanisms underlying the L-glutamine-induced increase in Ca2+ and cAMP intracellular concentrations ([Ca2+]i and [cAMP]i, respectively) in murine enteroendocrine L cell line GLUTag cells. Application of L-glutamine to cells under low extracellular [Na+] conditions, which inhibited the function of the sodium-coupled L-glutamine transporter, did not induce an increase in [Ca2+]i. Application of G protein-coupled receptor family C group 6 member A and calcium-sensing receptor antagonist showed little effect on [Ca2+]i and [cAMP]i; however, taste receptor type 1 member 3 (TAS1R3) antagonist suppressed the increase in [cAMP]i. To elucidate the function of TAS1R3, which forms a heterodimeric umami receptor with taste receptor type 1 member 1 (TAS1R1), we generated TAS1R1 and TAS1R3 mutant GLUTag cells using the CRISPR/Cas9 system. TAS1R1 mutant GLUTag cells exhibited L-glutamine-induced increase in [cAMP]i, whereas some TAS1R3 mutant GLUTag cells did not exhibit L-glutamine-induced increase in [cAMP]i and GLP-1 secretion. These findings suggest that TAS1R3 is important for L-glutamine-induced increase in [cAMP]i and GLP-1 secretion. Thus, TAS1R3 may be coupled with Gs and related to cAMP regulation.

Shaped silicon wafers obtained by hot plastic deformation: performance evaluation for future astronomical x-ray telescopes.

In order to develop lightweight and high angular resolution x-ray mirrors, we have investigated hot plastic deformation of 4 in. silicon (111) wafers. A sample wafer was deformed using hemispherical dies with a curvature radius of 1000 mm. The measured radius of the deformed wafer was 1030 mm, suggesting that further conditioning is indispensable for better shaping. For the first time to our knowledge, x-ray reflection on a deformed wafer was detected at Al K(alpha) 1.49 keV. An estimated surface roughness of <1 nm from the x-ray reflection profile was comparable to that of a bare silicon wafer without deformation. Hence, no significant degradation of the microroughness was seen.

Wave-dispersive x-ray spectrometer for simultaneous acquisition of several characteristic lines based on strongly and accurately shaped Ge crystal.

Si and Ge are widely used as analyzing crystals for x-rays. Drastic and accurate shaping of Si or Ge gives significant advance in the x-ray field, although covalently bonded Si or Ge crystals have long been believed to be not deformable to various shapes. Recently, we developed a deformation technique for obtaining strongly and accurately shaped Si or Ge wafers of high crystal quality, and the use of the deformed wafer made it possible to produce fine-focused x-rays. In the present study, we prepared a cylindrical Ge wafer with a radius of curvature of 50 mm, and acquired fluorescent x-rays simultaneously from four elements by combining the cylindrical Ge wafer with a position-sensitive detector. The energy resolution of the x-ray fluorescence spectrum was as good as that obtained using a flat single crystal, and its gain was over 100. The demonstration of the simultaneous acquisition of high-resolution x-ray fluorescence spectra indicated various possibilities of x-ray spectrometry, such as one-shot x-ray spectroscopy and highly efficient wave-dispersive x-ray spectrometers.

De novo UNC13B mutation identified in a bipolar disorder patient increases a rare exon-skipping variant.

AIM: We previously performed the first trio-based exome study for bipolar disorder and identified 71 de novo mutations. Among these mutations, the only mutation located at the splice donor site was in UNC13B. We focused on and analyzed the functions of the mutation. METHODS: In order to analyze the functional alterations, due to the mutation, we performed a minigene splicing assay. KEY RESULTS: We found that the mutation caused the loss of a wild-type splicing variant, which was consistent with the computational splice prediction, and that an exon-skipping variant increased significantly. The exon-skipping variant also existed in the wild-type minigene, although it was rare. Hence, we validated the expression of the exon-skipping variant using total RNAs derived from the human cerebral cortex. We showed the possibility that the exon-skipping variant was rare, but expressed even in those that do not carry the mutation. CONCLUSIONS: Based on our results, we suggest that an abnormal splicing pattern of UNC13B occurred in the patient, which could be related to the pathophysiology of bipolar disorder.

Quantitative evaluation of incomplete preweaning lethality in mice by using the CRISPR/Cas9 system.

Various molecular biology techniques implementing genome editing have made it possible to generate mouse mutants for nearly all known genes; as a result, the International Mouse Phenotyping Consortium (IMPC) database listing the phenotypes of genetically modified mice has been established. Among mouse phenotypes, lethality is crucial to evaluate the importance of genes in mouse survival. Although many genes are reported to show "preweaning lethality, incomplete penetrance" in the IMPC database, the survival rates of homozygous knockout mice are highly variable. Here, we propose the lethal allele index (LAI), the ratio of the observed number of mice with homozygous knockout (KO) to the theoretically predicted number of homozygous KO mice, as a simple quantitative indicator of preweaning lethality. Among the mice mutants registered as incompletely lethal in IMPC, the LAI calculated from the genotypes of F1 mice tended to be lower in disease-related genes, and correlated with the frequency of loss-of-function (LOF) alleles in humans. In genome-edited mice using CRISPR/Cas9, the number of mice with homozygous frameshift alleles seemed to be associated with lethality. We edited the Ehd1 gene in cell lines as well as mice using CRISPR/Cas9, and found that the genotype distribution was significantly different. The LAI calculated from these data was similar to the value calculated from the IMPC data. These findings support the potential usefulness of the LAI as an index of preweaning lethality in genome-edited mice.

Molecular motor KIF1C is not essential for mouse survival and motor-dependent retrograde Golgi apparatus-to-endoplasmic reticulum transport.

KIF1C is a new member of the kinesin superfamily of proteins (KIFs), which act as microtubule-based molecular motors involved in intracellular transport. We cloned full-length mouse kif1C cDNA, which turned out to have a high homology to a mitochondrial motor KIF1Balpha and to be expressed ubiquitously. To investigate the in vivo significance of KIF1C, we generated kif1C(-/-) mice by knocking in the beta-galactosidase gene into the motor domain of kif1C gene. On staining of LacZ, we detected its expression in the heart, liver, hippocampus, and cerebellum. Unexpectedly, kif1C(-/-) mice were viable and showed no obvious abnormalities. Because immunocytochemistry showed partial colocalization of KIF1C with the Golgi marker protein, we compared the organelle distribution in primary lung fibroblasts from kif1C(+/+) and kif1C(-/-) mice. We found that there was no significant difference in the distribution of the Golgi apparatus or in the transport from the Golgi apparatus to the endoplasmic reticulum (ER) facilitated by brefeldin A between the two cells. This retrograde membrane transport was further confirmed to be normal by time-lapse analysis. Consequently, KIF1C is dispensable for the motor-dependent retrograde transport from the Golgi apparatus to the ER.

The effects of caregiving resources on the incidence of depression over one year in family caregivers of disabled elderly.

The purpose of the study was to investigate the over-time effects of physical, psychological and social resources on the incidence of depression in family caregivers of the disabled elderly. Data were collected twice at a one-year interval from 1,141 primary caregivers of a disabled older person in an urban area of Japan using a self-reported questionnaire survey. The questionnaire included physical health as an indicator of physical resources, caregiving satisfaction and intention to care as indicators of psychological resources, and instrumental and emotional support network and formal home care service utilization as indicators of social resources. The mental health outcome measure was the General Health Questionnaire 12-item version (GHQ-12). Complete data on 235 non-depressed female caregivers were separated into 3 groups according to the relationship type (wife, daughter and daughter-in-law) and analyzed separately. Multivariate logistic regression models controlling for duration of caregiving, care-recipient's gender, ADL dependency and behavioral problems demonstrated that significant predictors of depression were caregiving satisfaction and intention to care in wives, caregiving satisfaction in daughters, and physical health and emotional support network in daughters-in-law. Noteworthy, intention to care increased the risk of depression in wives, while decreasing the risk of depression in daughters-in-law. The findings indicate that the effects of caregivers' resources on mental health may differ by relationship type.

Relationships of parenting strain and mental health with family needs in mothers of severely handicapped school-aged children suffering from cerebral palsy.

OBJECTIVE: The study was designed to clarify relationships of family needs of mothers of school-aged children suffering from cerebral palsy with the parenting strain and mental health. METHODS: The subjects were 249 mothers of cerebral palsy children from schools for the physically handicapped in Japan. The survey item consisted of sex and age of the children and age, family needs, parenting strain, and mental health of the mothers. Family needs of the mothers were determined according to "The Family Needs Survey". Parenting strain was assessed according to the "Parenting Strain Index for Parents with Disabled Children". Mental health was measured according to "General Health Questionaire-12". In the statistical analysis, an indirect model, with the parenting strain and family needs as the primary and secondary factor, respectively was postulated for mother's mental health, and fit of the model to the data was investigated. RESULTS: The Comparative Fit Index (CFI) was 0.962, the Tucker-Lewis Index (TLI) was 0.977, and the Root Mean Square Error of Approximation (RMSEA) was 0.058; these indices were statistically within the tolerance range. The path coefficient of correlation of the parenting strain with the family needs was 0.656, and the path coefficient of the parenting strain with mental health was 0.406; both were statistically significant. CONCLUSION: Relationships between family needs of mothers of cerebral palsy children from schools for the physically handicapped children and the mothers' parenting strain and mental health were indicated. The findings suggested that in order to develop and implement social intervention strategies for reducing mothers' parenting strain and providing solutions, it is imperative to extensively consider what family needs are and what solutions are required to resolve those needs.

Mitochondrial complex I activity is significantly decreased in a patient with maternally inherited type 2 diabetes mellitus and hypertrophic cardiomyopathy associated with mitochondrial DNA C3310T mutation: a cybrid study.

Mitochondrial respiratory function in a patient with maternally inherited type 2 diabetes mellitus and hypertrophic cardiomyopathy associated with heteroplasmic mitochondrial DNA (mtDNA) C3310T mutation, which replaces the second amino acid of NADH dehydrogenase 1 (ND1) from a hydrophobic Proline to a hydrophilic Serine, was investigated. Mitochondrial respiratory function solely due to mtDNA C3310T mutation was investigated in cybrid system by the fusion of mtDNA-deleted (rho(0)) HeLa cells and exogenous mtDNA either from the proband or from controls. Total oxygen consumption of the proband cybrid cells was significantly decreased compared with those of controls (2.468+/-0.475 versus 2.871+/-0.484 micromol/h/10(7) cells, p=0.0392). Mitochondrial respiratory chain complex I activity of the proband cybrid cells was also significantly decreased compared with those of controls (0.191+/-0.080 versus 0.288+/-0.113 micromol/h/mg protein, p=0.0223). Furthermore, ATP content in the proband cybrid cells was also significantly decreased compared with those in controls (1.119+/-0.344 versus 1.419+/-0.378 pmol/10(5) cells, p=0.044). The present study indicates that mtDNA C3310T mutation may be a pathogenic mutation of maternally inherited type 2 diabetes mellitus and hypertrophic cardiomyopathy in the proband and the family.

[Factors affecting WHOQOL-26 in community-dwelling patients with schizophrenia].

OBJECTIVE: Schizophrenic patients' quality of life (QOL) has become increasingly important due to shift of mental health care from hospitals to communities. This paper describes a longitudinal study conducted to clarify relationships among the QOL, self-esteem, depressive mood, and uncooperativeness of schizophrenic patients identified in the authors' previous crosssectional study. METHODS: Subjects were 61 schizophrenic patients attending day care at mental hospitals. They were assessed initially, and again after a 12-month follow-up. The assessment was carried out using the Rosenberg Self-Esteem Scale, WHOQOL-26 Scale, and the Brief Psychiatric Rating Scale, and included personal characteristics. Covariance structure analysis (Synchronous Effects Model) was conducted to clarify the relationships between self-esteem and the WHOQOL-26 Scale, and between psychiatric states (depressive mood and uncooperativeness) and self-esteem, while controlling for subjects' individual characteristics and use of antipsychotics as confounding factors. RESULTS: The results indicated that self-esteem had a significantly positive effect on the WHOQOL-26 Scale while depressive mood and uncooperativeness were without significant effects. CONCLUSIONS: The results provide evidence that the enhancement and maintenance of self-esteem may be an effective method of improving WHOQOL-26 in schizophrenic patients.